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A defining histopathologic feature of Taylor-type cortical dysplasia (CD) is the presence of cytomegalic neurons and balloon cells. Most cytomegalic neurons appear to be pyramidal-shaped and glutamatergic. The present study demonstrates the presence of cytomegalic GABAergic interneurons in a subset of pediatric patients with severe CD. Cortical tissue samples from children with mild, severe, and non-CD pathologies were examined using morphologic and electrophysiologic techniques. By using in vitro slices, cytomegalic cells with characteristics consistent with interneurons were found in 6 of 10 patients with severe CD. Biocytin labeling demonstrated that cytomegalic interneurons had more dendrites than normal-appearing interneurons. Whole-cell patch clamp recordings showed that cytomegalic interneurons had increased membrane capacitance and time constant compared with normal-appearing interneurons. They also displayed signs of cellular hyperexcitability, evidenced by increased firing rates, decreased action potential inactivation, and the occurrence of spontaneous membrane depolarizations. Single-cell reverse transcription-polymerase chain reaction and immunohistochemistry for GABAergic markers provided further evidence that these cells were probably cytomegalic interneurons. The pathophysiologic significance of GABAergic cytomegalic interneurons in severe CD tissue is unknown, but they could inhibit glutamatergic cytomegalic pyramidal neurons, or contribute to the synchronization of neuronal networks and the propagation of ictal activity in a subset of pediatric patients with severe CD.

A new method for enhancing MRI contrast between gray matter (GM) and white matter (WM) in epilepsy surgery patients with symptomatic lesions is presented. This method uses the radiation damping feedback interaction in high-field MRI to amplify contrast due to small differences in resonance frequency in GM and WM corresponding to variations in tissue susceptibility. High-resolution radiation damping-enhanced (RD) images of in vitro brain tissue from five patients were acquired at 14 T and compared with corresponding conventional T(1)-, T(2) (*)-, and proton density (PD)-weighted images. The RD images yielded a six times better contrast-to-noise ratio (CNR = 44.8) on average than the best optimized T(1)-weighted (CNR = 7.92), T(2) (*)-weighted (CNR = 4.20), and PD-weighted images (CNR = 2.52). Regional analysis of the signal as a function of evolution time and initial pulse flip angle, and comparison with numerical simulations confirmed that radiation damping was responsible for the observed signal growth. The time evolution of the signal in different tissue regions was also used to identify subtle changes in tissue composition that were not revealed in conventional MR images. RD contrast is compared with conventional MR methods for separating different tissue types, and its value and limitations are discussed.

In paediatric epilepsy surgery patients with hemimegalencephaly (HME; n = 23), this study compared clinical, neuroimaging and pathologic features to discern potential mechanisms for suboptimal post-hemispherectomy developmental outcomes and structural pathogenesis. MRI measured affected and non-affected cerebral hemisphere volumes for HME and non-HME cases, including monozygotic twins where one sibling had HME. Staining against neuronal nuclei (NeuN) determined grey and white matter cell densities and sizes in HME and autopsy cases, including the non-affected side of a HME surgical/autopsy case. By MRI, the affected hemisphere was larger and the non-affected side smaller in HME compared with non-HME children. The affected HME side showed enlarged abnormal deep grey and white matter structures and/or T2-weighted hypointensity in the subcortical white matter in 75% of cases, suggestive of excessive pre-natal neurogenesis and heterotopias. Histopathological examination of the affected HME side revealed immature-appearing neurons in 70%, polymicrogyria (PMG) in 61% and balloon cells in 45% of cases. Compared with autopsy cases, in HME children NeuN cell densities on the affected side were increased in the molecular layer and upper cortex (+244 to +18%), decreased in lower cortical layers (-35%) and increased in the white matter (+139 to +149%). Deep grey matter MRI abnormalities and/or T2-weighted white matter hypointensity correlated with the presence of immature-appearing neurons and PMG on histopathology, decreased NeuN cell densities in lower cortical layers and a positive history of infantile spasms. Post-surgery seizure control was associated with decreased NeuN densities in the molecular layer. In young children with HME and epilepsy, these findings indicate that there are bilateral cerebral hemispheric abnormalities and contralateral hemimicrencephaly is a likely explanation for poorer post-surgery seizure control and cognitive outcomes. In addition, our findings support the hypothesis that HME pathogenesis probably involves somatic mutations that affect each developing cerebral hemisphere differently with more neurons than expected on the HME side.

Seizures in cortical dysplasia (CD) could be from cytomegalic neurons and balloon cells acting as epileptic ‘pacemakers’, or abnormal neurotransmission. This study examined these hypotheses using in vitro electrophysiological techniques to determine intrinsic membrane properties and spontaneous glutamatergic and GABAergic synaptic activity for normal-pyramidal neurons, cytomegalic neurons and balloon cells from 67 neocortical sites originating from 43 CD patients (ages 0.2–14 years). Magnetic resonance imaging (MRI), 18fluoro-2-deoxyglucose positron emission tomography (FDG-PET) and electrocorticography graded cortical sample sites from least to worst CD abnormality. Results found that cytomegalic neurons and balloon cells were observed more frequently in areas of severe CD compared with mild or normal CD regions as assessed by FDG-PET/MRI. Cytomegalic neurons (but not balloon cells) correlated with the worst electrocorticography scores. Electrophysiological recordings demonstrated that cytomegalic and normal-pyramidal neurons displayed similar firing properties without intrinsic bursting. By contrast, balloon cells were electrically silent. Normal-pyramidal and cytomegalic neurons displayed decreased spontaneous glutamatergic synaptic activity in areas of severe FDG-PET/MRI abnormalities compared with normal regions, while GABAergic activity was unaltered. In CD, these findings indicate that cytomegalic neurons (but not balloon cells) might contribute to epileptogenesis, but are not likely to be ‘pacemaker’ cells capable of spontaneous paroxysmal depolarizations. Furthermore, there was more GABA relative to glutamate synaptic neurotransmission in areas of severe CD. Thus, in CD tissue alternate mechanisms of epileptogenesis should be considered, and we suggest that GABAergic synaptic circuits interacting with cytomegalic and normal-pyramidal neurons with immature receptor properties might contribute to seizure generation.

Summary: Purpose: Acute postoperative seizures (APOSs) are those that occur in the first 7 to 10 days after surgery, and previous studies in temporal lobe epilepsy patients support the notion that APOSs may foretell failure of long-term seizure control. It is unknown whether APOSs also predict seizure outcome or hospital course after hemispherectomy. Methods: Hemispherectomy patients (n = 114) were studied retrospectively and subdivided into the following groups: No APOSs, 1 to 5 APOSs, or >5 APOSs. Intensive care unit (ICU) nursing staff or family members reported and described the APOS events. APOS categories were compared with pre- and postsurgery clinical variables abstracted from the medical record. Results: APOSs occurred in 22.6% of hemispherectomy patients. Compared with the 0 and 1 to 5 APOS groups, patients with >5 APOS showed (a) longer seizure durations before surgery, (b) longer hospitalizations, (c) later oral food intake, (d) more frequent lumbar punctures, (e) worse seizure control at 0.5 and 1 year after surgery, (f) more antiepileptic drug (AED) use at 2 and 5 years after surgery, and (g) higher reoperation rate. No similar differences were found between the 0 and 1 to 5 APOS groups. The day of the APOS, whether the APOS was typical of preoperative seizures, and postsurgery scalp EEG did not predict long-term seizure control. APOS patients in the 1 to 5 and >5 groups had lower pre- and postsurgery Vineland developmental quotients compared with those without an APOS. Conclusions: Hemispherectomy patients with >5 APOSs had a more prolonged and complicated hospital course and worse postsurgery seizure control, more AED use, and higher reoperation rate than did patients with 0 or 1 to 5 APOSs. Thus the number of APOSs was a predictor of postsurgery seizure control and can be used to counsel patients and families about prognosis after hemispherectomy.

The subunit composition of glutamate receptors affects their functional properties, and could contribute to abnormal electrophysiology in pediatric cortical dysplasia (CD). We examined electrophysiological responses and subunit assembly of N-methyl-D-aspartate (NMDA) receptors in acutely dissociated normal-appearing pyramidal and cytomegalic neurons from CD tissue and normal-appearing pyramidal neurons from non-CD tissue. In most cytomegalic and approximately 30% of normal-appearing pyramidal neurons from CD tissue, NMDA currents showed decreased Mg(2+) sensitivity compared with neurons from non-CD tissue. Ifenprodil had less effect in CD compared with non-CD neurons, indicating a functional loss of NR2B subunits. NMDA-evoked current density was decreased in cytomegalic compared with normal-appearing neurons. Single-cell reverse transcriptase polymerase chain reaction showed that all non-CD neurons expressed NR2B subunit mRNA. By comparison, 22% of pyramidal neurons in CD tissue lacked NR2B mRNA. Immunofluorescence showed a decrease in NR2B subunit expression in cytomegalic neurons and a subset of normal-appearing pyramidal neurons from CD tissue. Taken together, these results demonstrate the presence of NMDA receptors with altered subunit composition and Mg(2+) sensitivity that could contribute to functional abnormalities in CD.

Changes in the expression of ion channels, contributing to altered neuronal excitability, are emerging as possible mechanisms in the development of certain human epilepsies. In previous immature rodent studies of experimental prolonged febrile seizures, isoform-specific changes in the expression of hyperpolarization-activated cyclic nucleotide-gated cation channels (HCNs) correlated with long-lasting hippocampal hyperexcitability and enhanced seizure susceptibility. Prolonged early-life seizures commonly precede human temporal lobe epilepsy (TLE), suggesting that transcriptional dysregulation of HCNs might contribute to the epileptogenic process. Therefore, we determined whether HCN isoform expression was modified in hippocampi of individuals with TLE. HCN1 and HCN2 expression were measured usingin situhybridization and immunocytochemistry in hippocampi from three groups: TLE with hippocampal sclerosis (HS;n= 17), epileptic hippocampi without HS, or non-HS (NHS;n= 10), and autopsy material (n= 10). The results obtained in chronic human epilepsy were validated by examining hippocampi from the pilocarpine model of chronic TLE.In autopsy and most NHS hippocampi, HCN1 mRNA expression was substantial in pyramidal cell layers and lower in dentate gyrus granule cells (GCs). In contrast, HCN1 mRNA expression over the GC layer and in individual GCs from epileptic hippocampus was markedly increased once GC neuronal density was reduced by >50%. HCN1 mRNA changes were accompanied by enhanced immunoreactivity in the GC dendritic fields and more modest changes in HCN2 mRNA expression. Furthermore, similar robust and isoform-selective augmentation of HCN1 mRNA expression was evident also in the pilocarpine animal model of TLE. These findings indicate that the expression of HCN isoforms is dynamically regulated in human as well as in experimental hippocampal epilepsy. After experimental febrile seizures (i.e., early in the epileptogenic process), the preserved and augmented inhibition onto principal cells may lead to reduced HCN1 expression. In contrast, in chronic epileptic HS hippocampus studied here, the profound loss of interneuronal and principal cell populations and consequent reduced inhibition, coupled with increased dendritic excitation of surviving GCs, might provoke a “compensatory” enhancement of HCN1 mRNA and protein expression.

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Objective: In children with and without infantile spasms, this study determined brain volumes and cell densities in epilepsy surgery patients with tuberous sclerosis complex (TSC) and cortical dysplasia with balloon cells (CD). Methods: We compared TSC (n = 18) and CD (n = 17) patients with normal/autopsy controls (n = 20) for MRI gray and white matter volumes and neuronal nuclei (NeuN) cell densities. Results: In patients without a history of infantile spasms, TSC cases showed decreased gray and white matter volumes (−16%). In cases with a history of infantile spasms, both CD (−25%) and TSC (−35%) patients showed microencephaly. This was confirmed in monozygotic twins with TSC, where the twin with a history of spasms had cerebral volumes less (−16%) than the twin without a history of seizures. Regardless of seizure history, TSC patients showed decreased NeuN cell densities in lower gray matter (−36%), whereas CD patients had increased densities in upper cortical (+52%) and white matter regions (+65%). For TSC patients, decreased lower gray matter NeuN densities correlated with reduced MRI volumes. Conclusions: Patients with tuberous sclerosis without spasms showed microencephaly associated with decreased cortical neuronal densities. In contrast, cortical dysplasia patients without spasms were normocephalic with increased cell densities. This supports the concept that tuberous sclerosis and cortical dysplasia have different pathogenetic mechanisms despite similarities in refractory epilepsy and postnatal histopathology. Furthermore, a history of infantile spasms was associated with reduced cerebral volumes in both cortical dysplasia and tuberous sclerosis patients, suggesting that spasms or their treatment may contribute to microencephaly independent of etiology.

Are the organic molecules crucial for life on Earth abundant in early-epoch galaxies? To address this, we searched for organic molecules in extragalactic sources via their absorption features, known as diffuse interstellar bands (DIBs). There is strong evidence that DIBs are associated with polycyclic aromatic hydrocarbons (PAHs) and carbon chains. Galaxies with a preponderance of DIBs may be the most likely places in which to expect life. We use the method of quasar absorption lines to probe intervening early-epoch galaxies for the DIBs. We present the equivalent width measurements of DIBs in one neutral hydrogen (HI) abundant galaxy and limits for five DIB bands in six other HI-rich galaxies (damped Lyman-alpha systems--DLAs). Our results reveal that HI-rich galaxies are dust poor and have significantly lower reddening than known DIB-rich Milky Way environments. We find that DIBs in HI-rich galaxies do not show the same correlation with hydrogen abundance as observed in the Milky Way; the extragalactic DIBs are underabundant by as much as 10 times. The lower limit gas-to-dust ratios of four of the HI-rich early epoch galaxies are much higher than the gas-to-dust ratios found in the Milky Way. Our results suggest that the organic molecules responsible for the DIBs are underabundant in HI-rich early epoch galaxies relative to the Milky Way., Comment: 6 pages, 2 figures

In epilepsy patients with cortical dysplasia (CD), this study determined the probable ontogenetic timing of pathogenesis based on the number, location and appearance of neurons. Magnetic resonance imaging (MRI) determined gray and white matter volumes of affected and non-affected cerebral hemispheres, and gray and white matter neuronal-nuclear protein (NeuN) densities and sizes were assessed in epilepsy surgery patients (0.2-38 years) with CD (n = 25) and non-CD etiologies (n = 14), and compared with autopsy cases (n = 13; 0-33 years). Pathology group, seizure type and age at surgery were compared against MRI and NeuN data. CD patients demonstrated increased MRI cerebral (3%) and gray matter (8%) volumes of the affected compared with non-affected cerebral hemisphere, and increased layer 1 (131%), upper cortical (9-23%) and white matter (28-77%) NeuN densities compared with autopsy cases. Non-CD cases showed decreased cerebral volumes of the affected hemisphere (14-18%) without changes in NeuN densities. Compared with autopsy cases, in CD and non-CD patients, cortical neurons were hypertrophied. Patients with a history of infantile spasms had a 40% increase in the size of layer 1 neurons compared with cases without spasms. By age, regardless of pathology group, there were logarithmic increases in MRI cerebral and white matter volumes, logarithmic increases in the size of lower gray and superficial white matter neurons, and logarithmic decreases in gray and white matter neuronal densities. These results support the concept that there were more neurons than expected in layer 1, gray, and white matter of CD patients compared with non-CD and autopsy cases. In addition, the location and appearance of neurons are consistent with the hypothesis that CD is the consequence of abnormalities occurring late in corticoneurogenesis that involve excessive neurogenesis with retention of pre-plate cells in the molecular layer and subplate regions.

Cerebral hemispherectomy for intractable seizures has evolved over the past 50 years, and current operations focus less on brain resection and more on disconnection. In addition, cases involving cortical dysplasia and Rasmussen encephalitis are being identified and surgically treated in younger individuals. Few studies have been conducted to compare whether there are perioperative differences based on hemispherectomy technique and/or pathological substrate in pediatric patients with epilepsy.In this study the authors compared, stratified by disease, anatomical (37 cases) and Rasmussen functional hemispherectomy (32 cases) with a new modified lateral hemispherotomy (46 cases). Pathological processes included cortical dysplasia (55 cases), Rasmussen encephalitis (21 cases), infarction/ischemia (27 cases), and other/miscellaneous (12 cases). The authors found differences in perioperative clinical factors based on operative technique and/or pathological substrate. In terms of technique, the lateral hemispherotomy was associated with the least intraoperative blood loss, shortest intensive care unit stay, and lowest complication rate. The anatomical hemispherectomy was associated with the longest hospital stay, delayed oral food intake, highest postsurgery fevers, and the highest incidence of shunt requirement. The functional hemispherectomy was associated with the highest reoperation rate for recurrent seizures (25%). In terms of pathology, patients with cortical dysplasia were the youngest at surgery, suffered the greatest amount of blood loss, and required the longest operative/anesthesia times compared with the other pathologically defined groups. Postoperative seizure control (range 0.5-2 years) was not statistically different according to technique or disease process and was similar to that in cases of pediatric temporal lobe epilepsy.The authors found differences in perioperative risks and hospital course but not postsurgery seizure control, which vary by hemispherectomy technique and/or disease process. The modified lateral hemispherotomy approach offers various advantages related to operative blood loss and reoperation compared with anatomical and functional hemispherectomies that are especially relevant in younger patients with cortical dysplasia and Rasmussen encephalitis with small and/or malformed ventricles.

The Far Ultraviolet Spectroscopic Explorer satellite observes light in the far-ultraviolet spectral region, 905 - 1187 A with high spectral resolution. The instrument consists of four coaligned prime-focus telescopes and Rowland spectrographs with microchannel plate detectors. Two of the telescope channels use Al:LiF coatings for optimum reflectivity from approximately 1000 to 1187 A and the other two use SiC coatings for optimized throughput between 905 and 1105 A. The gratings are holographically ruled to largely correct for astigmatism and to minimize scattered light. The microchannel plate detectors have KBr photocathodes and use photon counting to achieve good quantum efficiency with low background signal. The sensitivity is sufficient to examine reddened lines of sight within the Milky Way as well as active galactic nuclei and QSOs for absorption line studies of both Milky Way and extra-galactic gas clouds. This spectral region contains a number of key scientific diagnostics, including O VI, H I, D I and the strong electronic transitions of H2 and HD., To appear in FUSE special issue of the Astrophysical Journal Letters. 6 pages + 4 figures